Crystals of piperidine derivatives, intermediates for production of the same, and process for producing the same

ABSTRACT

Monohydrate and trihydrate crystals of N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidino) ethyl)-1-formyl-4-piperidinecarboxamide hydrochloride having excellent stability.

This application is a continuation of application Ser. No. 08/735,696,filed Oct. 23, 1996.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to crystals ofN-(2(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidino)ethyl)-1-formyl-4-piperidinecarboxamidehydrochloride, intermediates for production of the same, and a processfor producing the same.

2. Description of the Background

N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidino)ethyl)-1-formyl-4-piperidinecarboxamidehydrochloride, hereinafter referred to as Compound (I) at times has theformula (I):

and exhibits anti-hypertensive activity as well as activity incontrolling platelet agglutination. Thus, this compound is useful inpharmaceutical preparations. However, crystals thereof are as yetunknown.

SUMMARY OF THE INVENTION

Accordingly, it is an object of the present invention to providecrystals ofN-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidino)ethyl)-1-formyl-4-piperidinecarboxamidehydrochloride.

It is also an object of the present invention to provide an intermediatecompound for preparing the compound of the formula (I).

It is, moveover, an object of the present invention to provide a processfor producing the compound of the formula

The above objects and others are provided by crystals ofN-(2-(4-(5H-dibenzo(a,d)cyclohepten-5-ylidene)-piperidino)ethyl)-1-formyl-4-piperidinecarboxamidehydrochloride monohydrate.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a powder X-ray diffraction pattern of monohydrate crystals.

FIG. 2 is a powder X-ray diffraction pattern of trihydrate crystals.

FIG. 3 is a powder X-ray diffraction pattern of α-type anhydridecrystals.

FIG. 4 is a powder X-ray diffraction pattern of β-type anhydridecrystals.

FIG. 5 is an infra-red (IR), absorption spectrum of monohydratecrystals.

FIG. 6 is an IR absorption spectrum of trihydrate crystals.

FIG. 7 is an IR absorption spectrum of α-type anhydride crystals.

FIG. 8 is an IR absorption spectrum of β-type anhydride crystals.

FIG. 9 is a graph showing curves of dissolution rates of monohydrate andtrihydrate crystals. The indication “” corresponds to a datum point ona curve of a dissolution rate of monohydrate crystals, and theindication “◯” corresponds to a datum point on a curve of a dissolutionrate of trihydrate crystals.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In accordance with the present invention, crystals ofN-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidino)ethyl)-1-formyl-4-piperidinecarboxamidehydrochloride are provided. More specifically, two types of crystals,each in the form of a hydrate, are provided. These crystals exhibitunexpected stability, while one of the crystals further exhibitsexcellent oral absorption and the other exhibits a high dissolutionrate. These surprising discoveries have led to the present invention.

In more detail, the present invention relates to crystals ofN-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidino)ethyl)-1-formyl-4-piperidinecarboxamidehydrochloride monohydrate, crystals ofN-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidino)ethyl)-1-formyl-4-piperidinecarboxamidehydrochloride trihydrate, and intermediates for production of the same,as well as a process for producing the same.

The principal characteristics of these crystals are shown below. PowderX-ray diffraction patterns are shown in FIGS. 1 to 4. FIG. 1 is a powderX-ray diffraction pattern of monohydrate crystals. FIG. 2 is a powderX-ray diffraction pattern of trihydrate crystals. FIG. 3 is a powderX-ray diffraction pattern of anhydride crystals which are anintermediate for production of the monohydrate crystals (hereinafterreferred to as α-type anhydride crystals). FIG. 4 is a powder X-raydiffraction pattern of anhydride crystals which are an intermediate forproduction of the trihydrate crystals (hereinafter referred to as β-typeanhydride crystals). The diffraction angles (2θ) and intensities of themain peaks are shown in Tables 1 to 4.

TABLE 1 2θ Intensity 6.3 medium 10.5 weak 11.3 medium 11.8 medium 12.8weak 13.3 weak 13.7 weak 14.3 medium 15.3 weak 16.1 weak 16.8 medium17.7 medium 18.1 weak 18.7 medium 19.6 medium 20.3 strong 20.7 medium21.2 strong 22.3 weak 22.8 medium 23.5 weak 24.4 weak 25.2 medium 25.6weak 26.0 medium 26.4 strong 28.6 weak

TABLE 2 2θ Intensity 6.0 medium 10.2 weak 10.4 weak 10.9 weak 11.8 weak12.2 weak 12.9 medium 13.4 weak 14.6 strong 16.3 weak 17.2 weak 18.2weak 19.4 weak 19.6 strong 19.8 medium 20.7 medium 21.4 weak 21.8 medium22.3 medium 22.9 strong 23.4 weak 24.1 medium 24.6 weak 26.0 weak 26.6medium 27.3 weak 27.8 medium 28.3 medium 29.1 medium 29.7 weak 30.6 weak32.3 medium

TABLE 3 2θ Intensity 6.3 medium 7.8 weak 9.4 weak 10.6 weak 11.3 medium11.8 medium 12.9 weak 13.3 weak 13.8 weak 14.4 weak 15.3 weak 16.0 weak16.9 medium 17.8 medium 18.1 weak 18.6 medium 19.4 strong 20.3 strong20.9 strong 22.3 weak 22.7 strong 23.6 weak 25.1 weak 25.4 weak 26.0medium 26.3 strong

TABLE 4 2θ Intensity 6.2 medium 7.8 weak 10.0 weak 10.8 weak 11.6 weak12.0 weak 12.8 medium 13.7 weak 14.5 weak 15.0 medium 15.6 medium 16.6weak 17.3 weak 18.0 medium 18.3 weak 18.9 weak 19.4 medium 20.6 medium21.0 weak 21.6 medium 22.4 strong 23.8 medium 25.2 weak 25.6 weak 27.2medium 27.9 strong 28.8 weak 29.4 medium 33.7 medium

IR absorption spectra are shown in FIGS. 5 to 8. No clear melting pointwas found for any of the above-mentioned four types of crystals.

The monohydrate crystals of Compound (I) in the present invention can beproduced as follows.

Generally, the method of producing Compound (I) is not particularlylimited. For example, this compound can be produced as schematicallyshown below using known reactants, reagents and reactions.

Compound (I) is dissolved in a mixed solvent of water with alcohol suchas methanol, ethanol or isopropanol, tetrahydrofuran or acetone, andthen crystallizing this compound through cooling or the like. At thispoint, the water content of the mixed solvent is preferably betweenabout 2 and 50% by weight. The thus-obtained wet crystals are dried toobtain α-type anhydride crystals. Then when α-type anhydride crystalsare kept under an appropriate temperature and appropriate humidity, drymonohydrate crystals can be obtained. At the humidity-controlling, thetemperature is between 20 and 100° C., preferably between about 25 and90° C., and the relative humidity is between about 10 and 100%,preferably between about 50 and 90%. The time utilized is between about30 minutes and 48 hours, more preferably between about 2 hour and 30hours. The phrase “humidity-control” means that crystals are kept ormaintained under a certain temperature and humidity as defined herein.

The α-type anhydride crystals can be obtained by heat-drying theabove-mentioned monohydrate crystals, or by dissolving the same crystalsin the above-mentioned mixed solvent having a water content of less than2% by weight, crystallizing the mixture, and drying the resultingcrystals, or by dispersing the amorphous substance in a solvent such asethyl acetate or acetone, treating the dispersion at from 10 to 50° C.for from 10 minutes to 48 hours, and after conversion to crystals,drying the crystals.

Further, the trihydrate crystals of Compound (I) of the presentinvention are hardly precipitated directly from the solvent. However,the trihydrate crystals can be obtained by precipitating the crystalsfrom an aqueous solution, and humidity-controlling the resulting β-typeanhydride crystals at an appropriate temperature and appropriatehumidity. For the humidity-controlling, the temperature is between about20 and 100° C., preferably between about 25 and 90° C., and the relativehumidity is between about 30 and 100%, preferably between 50 and 90%.

The time utilized is between about 30 minutes and 48 hours, morepreferably between about 2 hours and 30 hours.

The present invention will now be further illustrated by reference tothe following Examples. These Examples are provided solely for purposesof illustration and are not intended to be limitative.

EXAMPLES Production Example 1 Production ofN-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidino)ethyl)-1-formyl-4-piperidinecarboxamidehydrochloride

Step 1

2-Aminoethylbromide hydrobromide (35.77 g, 174.6 mmols) and 22.80 g(104.8 mmols) of di-tert-butyl dicarbonate were added to a mixed solventof 300 ml of ether and 300 ml of water. Subsequently, 44.00 g (523.8mmols) of sodium hydrogencarbonate were gradually added thereto, and thesolution was stirred overnight at room temperature. The ether layer waswashed with 80 ml of 1N hydrochloric acid and then with 80 ml of asaturated aqueous solution of sodium chloride, and dried over magnesiumsulfate to obtain 21.57 g of 2-tert-butoxycarbonylaminoethyl bromide.

Step 2

2-Tert-butoxycarbonylaminoethyl bromide (13.5 g, 60.0 mmols) wasdissolved in 900 ml of acetonitrile together with 8.1 g (30.0 mmols) of4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidine and 12.6 ml (90mmols) of triethylamine, and the mixture was reacted at 50° C. for 16hours. After the temperature was returned to room temperature and thesolvent was distilled off, the residue was dissolved in 900 ml of ethylacetate, and insoluble matters were filtered off. The ethyl acetatesolution was washed with 300 ml of 1N hydrochloric acid, with 300 ml of1N sodium hydroxide and with 300 ml of a saturated aqueous solution ofsodium chloride. After the resulting product was dried over magnesiumsulfate, the solvent was distilled off, and the residue was purifiedthrough silica-gel chromatography to obtain 10.8 g of 4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(2-tert-butoxycarbonylamino)ethyl) piperidine.

Step 3

4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-1-(2-tert-butoxycarbonylamino)ethyl)piperidine(8.47 g, 20.4 mmols) was dissolved in 100 ml of dichloromethane. Then,100 ml of 4N hydrochloric acid dioxane solution were added thereto, andthe resulting solution was stirred at room temperature for 1 hour. Thesolvent was distilled off to obtain 8.56 g of1-(2-aminoethyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidinedihydrochloride.

Step 4

1-(2-Aminoethyl)-4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidinedihydrochloride (7.89 g, 20.3 mmols) was dissolved in 200 ml ofdichloromethane. 1-Formylisonipecotic acid (3.68 g, 23.4 mmols), 15.3 ml(110.0 mmols) of triethylamine, 0.27 g (2.2 mmols) of4-dimethylaminopyridine and 5.5 g (28.6 mmols) of1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride were addedthereto, and the mixture was stirred overnight at room temperature.After the solvent was distilled off, the residue was dissolved in 100 mlof dichloromethane, and the solution was washed with 100 ml of 1Nhydrochloric acid, with 100 ml of 1N sodium hydroxide and with 50 ml ofa saturated aqueous solution of sodium chloride. The solvent wasdistilled off, and the residue was purified through silica-gelchromatography to obtain 5.9 g ofN-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidine)ethyl)-1-formyl-4-piperidinecarboxamide.

Step 5

N-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidine)ethyl)-1-formyl-4-piperidinecarboxamide(5.90 g, 13.0 mmols) was dissolved in 50 ml of ether. Four millilitersof 4N hydrochloric acid dioxane were added thereto dropwise in anice-water bath while being stirred. one hundred milliliters of etherwere added thereto, and the mixture was stirred for 1 minute. Then,insoluble matters were separated through filtration. The filtrate wasdried under reduced pressure at 80° C. for 8 hours to give 5.14 g ofN-(2-(4-(5H-dibenzo[a,b]cyclohepten-5-ylidene)-piperidine)ethyl)-1-formyl-4-piperidinecarboxamide hydrochloride. This compound was amorphous.

Example 1

Compound (I) (1.2 g) was dissolved in 3 ml of ethanol at 60° C., and thesolution was gradually cooled to 20° C. while being stirred. Thecrystals precipitated were collected through filtration, and were driedat 60° C. under reduced pressure to obtain 0.4 g of the dry crystals.Elemental analysis and powder X-ray diffraction pattern of the crystalsindicated that these crystals were α-type anhydride crystals.

Example 2

Compound (I) (0.5 g) was dispersed in 10 ml of ethyl acetate, and thedispersion was stirred at 40° C. for 48 hours. The crystals werecollected through filtration, and were dried at 60° C. under reducedpressure to obtain 0.48 g of the dry crystals. Elemental analysis andpowder X-ray diffraction pattern of the crystals indicated that thesecrystals were α-type anhydride crystals.

Example 3

The α-type anhydride crystals obtained in Example 1 were spread thin ona petri dish, and were allowed to stand in a vessel which had beencontrolled at 40° C. and relative humidity of 75%. After 24 hours, thecrystals were subjected to elemental analysis and powder X-raydiffraction, from which it was determined that the crystals weremonohydrate crystals.

Example 4

Compound (I) (77.5 g) was dissolved in 610 ml of ethanol at 20° C., and22 ml of water were added thereto. The solution was cooled to 10° C.while being stirred, and the reaction solution was further stirred for16 hours. The crystals formed were collected through filtration. At thistime, the crystals were monohydrate crystals. These crystals were driedat 70° C. under reduced pressure to obtain 61.54 g of α-type anhydridecrystals. The resulting crystals were allowed to stand overnight at roomtemperature in a desiccator which had been controlled at relativehumidity of 75% with a saturated aqueous solution of sodium chloride togive 63.8 g of the crystals. Elemental analysis and powder X-raydiffraction pattern of the crystals indicated that these crystals weremonohydrate crystals.

Example 5

One gram of Compound (I) was dissolved in 10 ml of water at 80° C., andthe solution was gradually cooled while being stirred. The cooling wasconducted until the temperature reached 20° C. The crystals precipitatedwere collected through filtration, and were dried overnight at 60° C.under reduced pressure to obtain 0.85 g of the dry crystals. Elementalanalysis and powder X-ray diffraction pattern of the crystals indicatedthat these crystals were β-type anhydride crystals.

Example 6

The β-type anhydride crystals obtained in Example 5 were spread thin ona petri dish, and were allowed to stand in a temperature and humiditychamber which had been controlled at 40° C. and relative humidity of75%. After 24 hours, the crystals were subjected to elemental analysisand powder X-ray diffraction, from which it was determined that thecrystals were trihydrate crystals.

Example 7

A suspension of compound (I) (53.6 g) in isopropyl alcohol was stirredat 53° C. in 30 min, and then gradually cooled to 20° C. while beingstirred. The crystals precipitated were collected through filtration,and were dried under reduced pressure to obtain 051.4 g of the anhydrouscrystals. The resulting crystals were allowed to stand overnight at roomtemperature in a desiccator which had been humidity-controlled atrelative humidity of 75% to gave 52.5 g of the crystals. Elementalanalysis and powder X-ray diffraction pattern of the crystals indicatedthat these crystals were monohydrate crystal.

Example 8

The α-type anhydride crystals (2718 g) prepared by a similar method ofExample 1 were powdered by mill, and were allowed to stand in a seal-upbox which had been controlled at 30° C. and relative humidity of 80%.After 23 hours, the crystals were subjected to elemental analysis andpowder X-ray diffraction, from which it was determined that the crystalswere monohydrate crystals (2776 g).

Test Example 1

Each of the monohydrate and trihydrate crystals of Compound (I) producedin Examples 4 and 6 was orally administered to a Beagle dog at a dose of3.0 mg/kg. After 30 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 6 hours,8 hours and 24 hours of the administration, the blood was collected, theconcentration of Compound (I) in the plasma was measured, and the areaunder plasma concentration curve (AUC) was obtained. When the ratio ofthe AUC value of oral administration to that of intravenousadministration was defined as bioavailability, the bioavailability ofthe monohydrate crystals was 73.4%, and that of the trihydrate crystalswas 49.6%. Thus, the bioavailability of the monohydrate crystals washigher than that of the trihydrate crystals, and the monohydratecrystals, thus, exhibited high oral absorption.

Test Example 2

Each 20 mg of the monohydrate and trihydrate crystals of Compound (I)produced in Examples 4 and 6 was added to 500 ml of a gastric juicemodel solution (JP-1 solution according to Japan Pharmacopeia) of 37°C., and the concentration of Compound (I) in the solution was measuredover the course of time. The results are shown in FIG. 9. From FIG. 9,it was estimated that the trihydrate crystals exhibited a highdissolution rate compared to the monohydrate crystals and are, thus,suited for the production of prompt release drug products.

The monohydrate and trihydrate crystals of the present invention exhibitsurprisingly high stability, as they remain chemically and physically,unchanged even after storage for 1 month. Further, the monohydratecrystals exhibit excellent oral absorption, while the trihydratecrystals exhibit a high dissolution rate, making it possible to formpreparations that meet various requirements. Still further, themonohydrate and trihydrate crystals of the present invention can beeasily produced from α-type anhydride crystals and β-type anhydridecrystals.

It will be understood that many changes and modifications may be made tothe above-described embodiments without departing from the spirit andscope of the present invention.

What is claimed as new and desired to be secured by Letters Patent ofthe United States is:
 1. Crystals ofN-(2-(4-(5H-dibenzo(a,d)cyclohepten-5-ylidene)-piperidino)ethyl)-1-formyl-4-piperidinecarboxamidehydrochloride trihydrate.
 2. The crystals of claim 1, wherein peaks arepresent at diffraction angles (20θ±0.1) of 14.6, 19.6, 21.8, 22.3, 22.9,24.1, 26.6 and 28.3° in powder X-ray diffraction.
 3. Crystals ofN-(2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidino)ethyl)-1-formyl-4-piperidinecarboxamidehydrochloride anhydride, wherein peaks are present at diffraction angles(20θ±0.1) of 12.8, 15.0, 19.4, 22.4, 23.8, 27.2 and 27.9° in powderX-ray diffraction.
 4. A process for producing the crystals ofN-(2-(4(5H-dibenzo[a,d]cyclohepten-5-ylidene)-piperidino)ethyl)1-formyl-4-piperidinecarboxamidehydrochloride trihydrate, which comprises crystallization of theanhydride of claim 3 in a temperature and humidity controlled chamber.5. The process of claim 4, wherein the temperature is maintained at from20 to 90° C.
 6. The process of claim 5, wherein the temperature ismaintained at from about 25° C. and 90° C.
 7. The process of claim 4,wherein the relative humidity is maintained at from 50 to 100%.
 8. Theprocess of claim 7, wherein the relative humidity is maintained at fromabout 50 to 90%.